The goal is to investigate brain systems that mediate cognitive, affective, and reward processing in humans and to determine how these systems are influenced by late life depression, by genetic risk factors associated with depression, and by experimental manipulations of serotonin levels. Behavioral challenge tasks will be use during functional magnetic resonance imaging (fMRI) to investigate four specific aims: (1) We will complete studies initiated in the current funding period that investigate the influence of vascular lesions upon the interaction of ventral systems for emotional regulation and dorsal systems for executive control in patients with late life depression. These on-going studies also include an assessment of current clinical status, and whether treatment has led to a remission from depression. (2) We will characterize genetic influences upon the neural processing of emotional and rewarding stimuli using a task developed in current period that measures activity in amygdala, ventromedial and orbital frontal cortex, and ventral frontal cortex, and a second task that measures activity in striatal, midbrain, and dorsal systems associated with decisions about rewards. (3) We will evaluate the effects of neurotransmitter levels upon the neural processing of emotional and rewarding stimuli. Neuroimaging and neurophysiological studies reveal correlations between measures of neuronal activity and measures of behavioral states (e.g., mood, decision preference, response time). Such correlations suggest functional relationships, but typically remain untested. To functionally probe the effects of emotional/reward systems upon executive processing systems, we will pharmacologically manipulate levels of the neurotransmitter serotonin using ATD. Observation of systematic shifts in mood, behavioral preferences, or sensitivity to reward outcomes would have profound implications for understanding phenotypic variation in behavior associated with conditions such as depression, addiction, and anxiety syndromes. (4) We will evaluate the effects of mood changes upon the neural processing of emotional and rewarding stimuli. A common consequence of depression is anhedonia, or the inability to derive pleasure (or other emotional reaction) from normally rewarding stimuli. We will use procedures developed in the current period to manipulate mood state over short time intervals, and we will investigate how transient negative mood influences activation in brain systems that process emotional and rewarding stimuli.